Sangamo Therapeutics CEO Sandy Macrae, PhD, paused momentarily early in his presentation at the recent J.P., Morgan 39th Healthcare Conference, recalling how his genome editing company achieved a key 2020 goal of seeing its lead pipeline candidate advance into a pivotal study: “Just to say, Phase III is a very proud moment for a company like Sangamo.”
Sangamo created giroctocogene fitelparvovec (SB-525 or PF-07055480), although its development is now led by Pfizer after Sangamo transferred its IND to the pharma giant in 2019. Last October, Pfizer dosed the first participant in the Phase III AFFINE trial (NCT04370054), designed to assess the gene therapy candidate in 60 men with moderately severe to severe hemophilia A. Data from AFFINE should be read out in 2022.
Sangamo’s hemophilia A therapy leads a pipeline of 17 wholly-owned and partnered genomic medicines—four in clinical phases; the rest, preclinical. In addition to clinical-phase gene therapies like SB-525 and wholly-owned ST-920 for Fabry disease, Sangamo candidates include seven ex vivo gene-edited cell therapy programs, two of them clinical: BIVV003 (sickle cell disease) and ST-400 (beta thalassemia), both partnered with Sanofi and expected to release Phase I/II data by year’s end.
Also in the pipeline are seven preclinical in vivo genome regulation treatments based on Sangamo’s zinc finger protein transcription factor (ZFP-TF) technology. They include a candidate for amyotrophic lateral sclerosis (ALS) linked to mutations in the C9ORF72 gene, partnered with Pfizer under a collaboration launched in 2018; a treatment for Huntington’s disease linked to CAG repeat expansion in the Huntingtin gene, partnered with Takeda Pharmaceutical; and a candidate for tauopathies that include Alzheimer’s disease (ST-501, partnered with Biogen).
Macrae sat down with GEN Edge to discuss Sangamo’s leading candidates and those expected to enter the clinic in 2021. (This interview has been lightly edited for length and clarity.)
GEN Edge: Pfizer announced promising updated Phase I/II results for giroctocogene fitelparvovec (SB-525) last December, notably sustained Factor VIII activity levels in patients treated with the gene therapy. How significant was that data?
Sandy Macrae: What I liked as a physician was how safe and well tolerated it was. The results that were important to patients are that they don’t need to take additional factor, they’re not having bleeds (with one exception), and their lives have been changed. The idea that they lived from fridge to fridge, worrying about factor and worrying how their life was going to happen, that has changed dramatically for these patients, whether it’s the BioMarin drug or the Pfizer/Sangamo one.
But it’s only five patients we’re talking about. We need to be careful to try and generalize from five to a whole population, which is why the Phase III trial needs to be done. We can’t know SB-525 more fully until and unless it goes through Phase III, and we see a larger population of patients treated for a long time. But all the signs are encouraging, and guide us to sustained benefit.
GEN Edge: How significant is SB-525 to the broader gene therapy field?
Macrae: I think this is a moment for gene therapy, because hemophilia A isn’t an ultra-rare disease, and it isn’t a lethal disease in small children, which is what the approved products have been so far. The FDA is being more thoughtful, more cautious perhaps, they’ll require good, well controlled data in more than one trial, and they’ll produce a label reflective of that. Then, the discussion becomes: Where does it fit in in the armamentarium of hemophilia doctors and patients?
That’s where we’re so pleased to have Pfizer leading this, because this is going to be a discussion with payers about the value to patients. And although the lifetime costs to patients is $6-7 million the last time I saw, that’s just a factor level. If you look at the total lifetime cost, it’s $25-30 million by the time you include all the hospital visits and consequences of their disease. If a simple once-and-done treatment that lasts for many years can take that away, it’s a benefit to the patient, it’s a benefit to society, and it’s a benefit to the whole community of hemophilia. This is an important moment in the first wave of genomic medicines.
GEN Edge: How has the challenge of dosing been handled to date? We’ve seen some clinical setbacks for some other gene therapies over the past year, which has rekindled this issue of how you dose.
Macrae: I’ve been more, I think, phlegmatic or even sanguine about this, because we’re right at the cutting edge of a new field. And each of the companies is testing different diseases where the benefit/risk of the therapy matters. Every time there’s an announcement of a safety finding or even an efficacy finding from one of our competitors or colleagues, we take time at Sangamo to go through the clinical pros and cons of what we can learn, what it means for our medicine: Is the risk benefit still positive? Some of the diseases that people are looking at are awful lethal diseases where the patients die of horrible things. It can be quite difficult to tease apart what’s the medicine, and what’s the disease, particularly when it’s open label studies, and very few patients.
I also think we have a responsibility to advance this field prudently, rather than rushing into diseases where the benefit risk is not so clear, because what we don’t want is another episode such as the unfortunate Jesse Geisinger, where there was a safety problem that led to delay and everything else benefiting other patients.
We spend a lot of time with patients. We bring them in—virtually now—to the company. They comment on every one of our protocols. They tell us what’s important to them, and they help us to do what’s right for a community that will have to make the decision themselves because if you imagine being a patient in one of these rare diseases, or a father of a patient in one of these rare diseases, the decision you’re having to make is such an important one. You’re consenting for life. You’re consenting for something that once it’s given to the patient stays with them, hopefully for the rest of their days. We can’t do this alone.
Therefore, although we do our very best to do an informed consent, we rely greatly on the patient support groups who help mentor and inform the patients, and make sure they make the right decision. We will get there, but we need to go prudently.
GEN Edge: With Pfizer running the Phase III AFFINE trial, where does Sangamo come in as a partner?
Macrae: We still have a joint steering committee with them. We still speak regularly to our friends at Pfizer, because we have a second product running with Pfizer for ALS. That’s one we’ve handed over to Pfizer as well. We turn down the gene only in the mutant allele, and we don’t touch the wild type [allele]. It’s molecular science fiction, and it shows the remarkable precision of the Sangamo technology. They’re very pleased to advance that forward.
GEN Edge: Speaking of the program in C9orf72-related ALS, where does that stand?
Macrae: It’s a hereditary form of ALS. It’s mostly a hereditary mutation that occurs occasionally as a spontaneous mutation. We’ve shown the Sangamo zinc finger protein-transcription factors previously for Huntington’s disease, a program currently with Takeda. Now with C9orf72, we’ve shown that we can land on the expanded mutation and turn it off, while at the same time we don’t alter the other allele that isn’t expanded, allowing that to keep expressing. It’s only possible, I believe, with our technology. We are always looking for diseases that have a similar challenge to best use our remarkable technology.
GEN Edge: A lot of Sangamo’s technology is being used in neurological indications like ALS. Is there a particular bent by Sangamo toward neurological disorders for the technology going forward?
Macrae: I think there’s a huge unmet need in neuroscience. I started my career in industry in neuroscience, so it’s something I’m passionate about. The advantage of our transcription factors is they don’t require the cell to be dividing. In fact, there’s a benefit because the cells are not dividing because it gives longevity of effect. [The transcription factors] can land anywhere near the promoter of the gene, and they can turn it on, as we’re doing with Novartis, or off as we’re doing with Biogen. We can control the level of on- and off-ness with great precision, and exquisitely work out the production or not of RNA, which then leads to the protein.
Other technologies demand that you need to know: What protein? Is it the monomeric form or the multimeric form? Is it the phosphorylated form? Or if they do the RNA, they’ve got to know which splice their insert is. The advantage of what we do is we go right back to the source. We turn on and off the tap that leads to all of this accumulation of everything from tau, and α-synuclein C9orf72 or something that is wholly owned by Sangamo in prion disease. We can turn off production of prion, which is a devastating disease.
GEN Edge: One application of Sangamo’s zinc finger protein transcription factor technology is ST-501, the candidate for tauopathies partnered with Biogen. How might that succeed where so many candidates have failed against Alzheimer’s?
Macrae: Many of the tau studies are targeting a form of tau: is it the phosphorylated form, the multimeric form, or the monomeric form? You have to make a call on which one is the right one to do. We go back to the source and we can control all tau. So, it really doesn’t matter what form it is that is the pathological one. We’re able to alter production of tau in all its forms. That’s the bit that’s most exciting, and that’s why Biogen decided to do such a big fundamental deal with us.
GEN Edge: What is the status of ST-502, the Parkinson’s disease candidate?
Macrae: In some patients, an alteration or mutation of α-synuclein is one of the things that is the cause of Parkinson’s disease. Again, in a way similar to tau, we’re going back to the source, and we’re turning off α-synuclein. And for those patients whose α-synuclein causes [Parkinson’s], it will be a huge benefit to them. But we believe it also could be a useful treatment for even prevention of progression for many patients with Parkinson’s disease.
In the end, that’s the Holy Grail of Parkinson’s treatment. It’s not just symptomatic treatment, which there are many ways to do, but involves large amounts of pharmacotherapy. It’s prevention of progression, and if you could do that, that would be a remarkable thing.
GEN Edge: Turning to cancer, there was talk last year of submitting an IND for KITE-037, the first product candidate developed by Sangamo with Kite, a Gilead Company, but that didn’t happen. Will the IND be submitted this year?
Macrae: Some of what happened last year was COVID-19, some of that was drug development, and some of it was the changes within Kite/Gilead. But it’s moving ahead. It will go to an IND and be in the clinic this year.
Our editing technology works. If you do it in a test tube or you do it in cells, it works beautifully every time. It’s a matter of getting enough of the editing technology into the cell you want to edit. That’s the advantage of cell therapy because you take the cells, you edit them, and you return them to the patient. And therefore CAR-T is the first place everyone’s going because oncology is a place of enormous medical need.
GEN Edge: Sangamo sought leadership in chimeric antigen receptor-modified regulatory T-cell (CAR-Treg) therapies for solid organ transplants when it acquired TxCell in 2018 for €72 million ($87 million). What promise does Sangamo see for Tregs in allogeneic autoimmune indications, and what will happen to TxCell’s lead candidate TX200 this year?
Macrae: The advantage of Tregs is you don’t need to know the causative antigen. You just need to know the localizing antigen, the thing that takes you to the place where the inflammation is.
Our first trial for TX200 is in HLA-A2 mismatched renal transplants, where patients that are HLA-A2 negative are given an A2 positive kidney. That happens in 20-25% of renal transplants. We created an autologous product for the moment where the CAR-Treg has an A2 localizing CAR on it. The only place that that exists in the patient’s body is in this new kidney they’ve got. And because the kidney is transplanted so close to the surface, we’ll be able to do biopsies of it, and we’ll be able to show that the CAR-Treg is localized activated and survives within the kidney.
It really will be a big benefit, I hope, to the patients, but it also is more a grand proof of concept for Tregs, because then that leads us into multiple sclerosis, inflammatory bowel disease, rheumatoid arthritis—it’s an enormous field, not a rare disease field. It moves Sangamo out of ultra-rare diseases into common diseases with large unmet medical needs.
GEN Edge: Why is Sangamo moving beyond rare diseases?
Macrae: We looked at the various diseases in the liver. There are 7,000 rare diseases in the liver, and there’s only about 20 of them that are sufficiently common that the trials are practical and, to be really honest, the return on investment for a company to develop it makes sense.
On top of that, you then have the number of companies that are in the liver space, each taking a slice of the pie. And no matter how much you want to get to the ultra-rare diseases, there’s only a handful of patients in the U.S., and it’s very hard to run the clinical trials. Once you’ve treated these handfuls of patients, you’ve treated all the patients that are in the U.S. So, it just doesn’t make sense.
Ultra-rare diseases is getting to be a very crowded space, and we don’t think it’s the sensible way forward. We are lucky that because of our technology, we can go to other places. We can move beyond delivery to the CNS to cell therapy. And once we solve delivery in other tissues, the number of places we can make a huge medical difference are enormous.
GEN Edge: In July, Sangamo announced an up to $795 million-plus collaboration with Novartis to develop gene regulation therapies for neurodevelopmental disorders using ZFP-TFs. What progress have Sangamo and Novartis made since the summer?
Macrae: We had our first kickoff meeting and Jay Bradner [MD, President] of NIBR [Novartis Institute for BioMedical Research] told everyone how passionate he was about this technology, and how excited he was by the collaboration. It’s unusual to see that level of involvement at the senior level.
As I’ve been telling you about tau and α-synuclein being turned off by our repressors, we also can add enhancers onto the zinc finger. Think about the zinc finger like a Swiss army knife. The zinc finger is the bit that localizes you to the zip code that you want to go. Then we have all kinds of functionality we can add on to the zinc finger. Is it a nuclease to edit? Is it a repressor? Is it an enhancer? Is it a base editor? Is it recombinase? Is it something to alter epigenetic editing? It’s simply a matter of attaching it on to the zinc fingers. The zinc fingers are so small that you have room to attach things to them and still get into an AAV, which isn’t true of CRISPR technology, because they struggle to get a CRISPR base editor into an AAV.
We’re very excited by the next wave of genomic medicines. We do gene therapy now to things in the liver, because it’s the practical thing to do, but the future of genomic medicines is far beyond that, and we’re sure we’ll be part of that future.
GEN Edge: Sangamo has been constructing cGMP manufacturing facilities in Brisbane, CA, and Valbonne, France. Will both be operational this year?
Macrae: We’ve completed the GMP facility for AAV in Brisbane. That was a great [construction] job; they did everything socially distanced and tested for COVID, and they hit their marks. We hope to have cell therapy operational in Brisbane by the end of the year. In Valbonne, we’re in the process of constructing a cell therapy facility by the end of 2021 or the beginning of 2022. In-house manufacturing is important. It not only allows you control of timing and cost, but it also allows you to develop better products because it’s in your own backyard and the scientists and the manufacturing people can get close together.